MON-280 - Overcoming Statin Intolerance in Heterozygous Familial Hypercholesterolemia: A Case of Creative Combination Therapy

Background: Familial hypercholesterolemia (FH) is a genetic disorder causing elevated LDL cholesterol with a prevalence of approximately 1:300. Mutations in the LDL receptor (LDLR) gene are the most common cause and result in the highest LDL-C levels. If untreated, FH leads to premature atherosclerotic cardiovascular disease (ASCVD) and increased risk of myocardial infarction (MI). Lifestyle modifications and statins to achieve LDL-C targets are the mainstay of FH management, making statin intolerance a significant therapeutic challenge.

Case Presentation: A 77-year-old female with genetically confirmed heterozygous FH and hypertension presented with extensive family history of hyperlipidemia (HLD) and ASCVD complications including stroke, MI, and sudden cardiac death in multiple first-degree relatives. Initially diagnosed with HLD in her twenties, she was started on statin therapy but developed severe myalgias and arthralgias, particularly affecting her shoulders and upper extremities. She reported intolerance to multiple statins at the lowest doses, experiencing severe muscle and joint pain. She also experienced similar myalgias with ezetimibe. She could tolerate rosuvastatin 10 mg but not higher doses. Her lipid control remained suboptimal with total cholesterol 391 mg/dL, HDL-C 38 mg/dL, LDL-C 324 mg/dL, and triglycerides (TG) 145 mg/dL in 9/2016.

Genetic testing revealed a heterozygous LDLR variant (c.2478del; p.Val827Serfs102). She was initiated on alirocumab in 2019, which reduced LDL-C from 264 mg/dL to 132 mg/dL, though this remained above goal of 70 mg/dL. Between 2019-2025, statin therapy was intermittent due to persistent myalgias. In 2020, she was diagnosed with polymyalgia rheumatica (PR) requiring corticosteroid therapy for two years, significantly worsening her lipid profile. After failed trials of fenofibrate and fish oil, low-dose rosuvastatin produced dramatic improvement with LDL-C reaching 57 mg/dL in 8/2023. However, a PR flare requiring statin discontinuation resulted in LDL-C rising above 100 mg/dL despite continued alirocumab and fish oil. She was ultimately stabilized on a combination regimen of rosuvastatin 2.5 mg every other day, alirocumab 150 mg subcutaneously every two weeks, and ezetimibe 10 mg daily, achieving total cholesterol 134 mg/dL, HDL-C 50 mg/dL, LDL-C 74 mg/dL, and TG 76 mg/dL.

Conclusion: This case demonstrates successful management of statin-intolerant FH through ultra-low-dose statin combined with PCSK9 inhibitor and ezetimibe therapy. It may be that this variant of FH responds well to this type of therapy. The case also highlights the challenges posed by concurrent inflammatory conditions requiring corticosteroids and emphasizes the importance of genetic testing, personalized treatment strategies, and creative combination therapy in achieving lipid targets in complex FH patients.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*